A5082148969- CAR-T cell therapy research
- Gene Regulatory Network Analysis
- Virus-based gene therapy research
- DNA Repair Mechanisms
- Immune Cell Function and Interaction
- Immunotherapy and Immune Responses
- Single-cell and spatial transcriptomics
- Carcinogens and Genotoxicity Assessment
- Cellular Mechanics and Interactions
- Evolution and Genetic Dynamics
- Plant Genetic and Mutation Studies
- Microbial Metabolic Engineering and Bioproduction
- Viral Infectious Diseases and Gene Expression in Insects
- Microtubule and mitosis dynamics
- Environmental and Social Impact Assessments
- Developmental Biology and Gene Regulation
- Air Quality and Health Impacts
- Health Systems, Economic Evaluations, Quality of Life
- 3D Printing in Biomedical Research
- Climate Change and Health Impacts
- Complement system in diseases
- Mathematical Biology Tumor Growth
- vaccines and immunoinformatics approaches
- PARP inhibition in cancer therapy
- Lymphoma Diagnosis and Treatment
Texas Children's Hospital
2022-2025
Baylor College of Medicine
2022-2025
Houston Methodist
2022-2025
Methodist Hospital
2023-2025
Public Health England
2016
University College London
2011-2016
UCL Australia
2015
Public Health Agency
2013
Collective cell migration is a mode of movement crucial for morphogenesis and cancer metastasis. However, little known about how migratory cells coordinate collectively. Here we show that mutual cell-cell attraction (named here coattraction) required to maintain cohesive clusters migrating mesenchymal cells. Coattraction can counterbalance the natural tendency disperse via mechanisms such as contact inhibition epithelial-to-mesenchymal transition. Neural crest are coattracted complement...
Collective cell migration is fundamental throughout development and in many diseases. Spatial confinement using micropatterns has been shown to promote collective vitro, but its effect vivo remains unclear. Combining computational experimental approaches, we show that the of neural crest cells (NCCs) depends on such confinement. We demonstrate may be imposed by spatiotemporal distribution a nonpermissive substrate provided versican, an extracellular matrix molecule previously proposed have...
Collective cell migration is a fundamental process, occurring during embryogenesis and cancer metastasis. Neural crest cells exhibit such coordinated migration, where aberrant motion can lead to fatality or dysfunction of the embryo. Migration involves at least two complementary mechanisms: contact inhibition locomotion (a repulsive interaction corresponding directional change upon with reciprocating cell), co-attraction mutual chemoattraction mechanism). Here, we develop employ...
The engineering of transcriptional networks presents many challenges due to the inherent uncertainty in system structure, changing cellular context, and stochasticity governing dynamics. One approach address these problems is design build systems that can function across a range conditions; they are robust their constituent components. Here we examine parametric robustness landscape oscillators, which underlie important processes such as circadian rhythms cell cycle, plus also serve model...
We show that a binary oncolytic/helper-dependent adenovirus (CAdVEC) both lyses tumor cells and locally expresses the proinflammatory cytokine IL-12 PD-L1 blocking antibody has potent antitumor activity in humanized mouse models. On basis of these preclinical studies, we treated four patients with single intratumoral injection an ultralow dose CAdVEC (NCT03740256), representing oncolytic more than 100-fold lower used previous trials. While caused no significant toxicities, it repolarized...
Genetic switches exhibit multistability, form the basis of epigenetic memory, and are found in natural decision making systems, such as cell fate determination developmental pathways. Synthetic genetic can be used for recording presence different environmental signals, changing phenotype using synthetic inputs building blocks higher-level sequential logic circuits. Understanding how multistable constructed they function within larger biological systems is therefore key to biology. Here we...
Raman spectroscopy (RS) is a powerful technique that permits the non‐destructive chemical analysis of cells and tissues without need for expensive complex sample preparation. To date, samples have been routinely mounted onto calcium fluoride (CaF 2 ) as this material possesses desired mechanical optical properties analysis, but CaF both brittle prevents from being adopted. Furthermore, scattering weak phenomenon provides no means increasing signal. For RS to be widely adopted, particularly...
Background The wider application of T cells targeting viral tumor-antigens via their native receptors is hampered by the failure to expand potent tumor-specific from patients. Here, we examine reasons for and solutions this failure, taking as our model preparation Epstein-Barr virus (EBV)-specific (EBVSTs) treatment EBV-positive lymphoma. EBVSTs could not be manufactured almost one-third patients, either because they failed expand, or expanded, but lacked EBV specificity. We identified an...
Chimeric antigen receptor T cells (CART) targeting lymphocyte antigens can induce cell fratricide and require additional engineering to mitigate self-damage. We demonstrate that the expression of a chimeric (CAR) CD5, prominent pan-T antigen, induces rapid internalization complete loss CD5 protein on cells, protecting them from self-targeting. Notably, exposure healthy malignant CD5.CART similar target transiently shielding cytotoxicity. However, this protection is short-lived, as sustained...
There is increasing appreciation of the proportion health burden that attributed to modifiable population exposure environmental hazards. To manage this avoidable in United Kingdom (UK), government policies and interventions are implemented. In practice, procedure interdisciplinary action multi-dimensional context. Here, we demonstrate how Multi Criteria Decision Analysis (MCDA) can be used as a decision support tool facilitate priority setting for public within local authorities. We combine...
<h2>ABSTRACT</h2> T cell receptor engineered (TCR T) therapies have shown recent efficacy against certain types of solid metastatic cancers. However, to extend TCR treat more patients across additional cancer types, new TCRs recognizing cancer-specific antigen targets are needed. Driver mutations in <i>AKT1, ESR1, PIK3CA</i>, and <i>TP53</i> common with breast (MBC) if immunogenic could serve as ideal tumor-specific for therapy this disease. Through IFN-γ ELISpot screening <i>in vitro</i>...
TPS2679 Background: Urgent therapies are needed for patients with refractory Human Epidermal Growth Factor Receptor 2 (HER2) positive solid malignancies. Our group has previously shown potent antitumor effect of a binary oncolytic/helper-dependent adenovirus (CAdVEC) dual expression IL-12 and PD-L1 blocker. Initial preclinical clinical studies direct tumor injection CAdVEC it to be safe result in increased infiltration CD8 T cells into the microenvironment, on locoregional distant metastatic...
DNA double-strand breaks are lesions that form during metabolism, replication and exposure to mutagens. When a break occurs one of number repair mechanisms is recruited, all which have differing propensities for mutational events. Despite being crucial importance, the relative contribution these their regulatory interactions remain be fully elucidated. Understanding processes will profound impact on our knowledge genomic instability, with implications across health, disease evolution. Here...
Abstract Background: Metastatic breast cancer (MBC) which causes significant morbidity and mortality worldwide is in need of more effective treatment regimens. In combination with chemotherapy, anti-PD1 antibody pembrolizumab has been shown to prolong progression-free survival (PFS) patients triple-negative subtype MBC (TN-MBC), however, its efficacy remains low for the other 80% MBC. MBC’s heterogenous pattern immune infiltration expression make it challenging treat single immunotherapeutic...
Abstract The engineering of transcriptional networks presents many challenges due to the inherent uncertainty in system structure, changing cellular context and stochasticity governing dynamics. One approach address these problems is design build systems that can function across a range conditions; they are robust their constituent components. Here we examine parametric robustness landscape oscillators, which underlie important processes such as circadian rhythms cell cycle, plus also serve...
Background Oncolytic adenoviruses (OAds) are the most clinically tested viral vectors for solid tumors. However, “Armed” OAds show limited antitumor effects in patients with various tumors even increased dosages and multiple injections. We developed a binary oncolytic/helper-dependent adenovirus system (CAdVEC), which coinfected an OAd non-replicating helper-dependent Ad (HDAd). recently demonstrated that single low-dose CAdVEC expressing interleukin-12, programmed death-ligand 1 blocker,...
Abstract DNA double-strand breaks are lesions that form during metabolism, replication and exposure to mutagens. When a break occurs one of number repair mechanisms is recruited, all which have differing propensities for mutational events. Despite being crucial importance, the relative contribution these their regulatory interactions remain be fully elucidated. Understanding processes will profound impact on our knowledge genomic instability, with implications across health, disease...
Abstract Genetic switches exhibit multistability, form the basis of epigenetic memory, and are found in natural decision making systems, such as cell fate determination developmental pathways. Synthetic genetic can be used for recording presence different environmental signals, changing phenotype using synthetic inputs building blocks higher-level sequential logic circuits. Understanding how multistable constructed they function within larger biological systems is therefore key to biology....
Multiple mechanisms contribute to the repair of double strand breaks (DSBs) and their relative contribution, interplay regulatory interactions remain be fully elucidated. The propensity mechanism activation directly affects distribution mutation within genome, so a better understanding collective pathways will have fundamental role in genome stability evolution. Current kinetic modeling approaches can emulate DSB but provide no predictions on dynamics back-up when cells become deficient at...
Chimeric antigen receptors (CARs) targeting lymphocyte antigens can induce T-cell fratricide and require additional engineering to mitigate self-damage. We demonstrate expression of a CAR CD5, prominent pan-T cell antigen, induces rapid internalization complete loss the CD5 protein on T cells protecting them from self-targeting. Notably, exposure healthy malignant CD5.CART induced similar target transiently shielding cytotoxicity. However, this protection was short-lived as sustained...
Background The range and complexity of environmental hazards to which populations are exposed is vast effects on health multi-faceted. In order capture potential in a meaningful way, they can be compared matched exposures outcomes, there need for systematic approach enable ranking scarce resources applied the most significant burden disease. Aim To develop systematic, quantitative risk assessment methodology identification prioritisation human inform epidemiological studies. Methods 1....